2-取代苯并恶唑类化合物作为强效抗炎剂：合成、分子对接及体内抗溃疡研究。
2-Substituted Benzoxazoles as Potent Anti-Inflammatory Agents: Synthesis, Molecular Docking and In vivo Anti-Ulcerogenic Studies.
机构信息
Faculty of Pharmacy, Capital University of Science and Technology, Islamabad 44000, Pakistan.
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan.
出版信息
Med Chem. 2022;18(7):791-809. doi: 10.2174/1573406418666211220125344.
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonly used therapeutic interventions of inflammation and pain that competitively inhibit the cyclooxygenase (COX) enzymes. Several side effects like gastrointestinal and renal toxicities are associated with the use of these drugs. The therapeutic anti-inflammatory benefits of NSAIDs are produced by the inhibition of COX-2 enzymes, while undesirable side effects arise from the inhibition of COX-1 enzymes.
OBJECTIVE
In the present study, a new series of 2-substituted benzoxazole derivatives 2(a-f) and 3(ae) were synthesized in our lab as potent anti-inflammatory agents with outstanding gastro-protective potential. The new analogs 2(a-f) and 3(a-e) were designed depending upon the literature review to serve as ligands for the development of selective COX-2 inhibitors.
METHODS
The synthesized analogs were characterized using different spectroscopic techniques (FTIR, HNMR, CNMR) and elemental analysis. All synthesized compounds were screened for their binding potential in the protein pocket of COX-2 and evaluated for their anti-inflammatory potential in animals using the carrageenan-induced paw edema method. Further 5 compounds were selected to assess the in vivo anti-ulcerogenic activity in an ethanol-induced anti-ulcer rat model.
RESULTS
Five compounds (2a, 2b, 3a, 3b and 3c) exhibited potent anti-inflammatory activity and significant binding potential in the COX-2 protein pocket. Similarly, these five compounds demonstrated a significant gastro-protective effect (**p<0.01) in comparison to the standard drug, Omeprazole.
CONCLUSION
Depending upon our results, we hypothesize that 2-substituted benzoxazole derivatives have excellent potential to serve as candidates for the development of selective anti-inflammatory agents (COX-2 inhibitors). However, further assessments are required to delineate their underlying mechanisms.
背景
非甾体抗炎药（NSAIDs）是常用的炎症和疼痛治疗干预措施，它们竞争性地抑制环氧化酶（COX）酶。这些药物的使用与一些副作用有关，如胃肠道和肾脏毒性。NSAIDs 的治疗抗炎益处是通过抑制 COX-2 酶产生的，而不良副作用则是由于抑制 COX-1 酶引起的。
目的
在本研究中，我们实验室合成了一系列新的 2-取代苯并恶唑衍生物 2(a-f)和 3(ae)，作为具有出色胃保护潜力的有效抗炎药物。新的类似物 2(a-f)和 3(a-e)是根据文献综述设计的，作为开发选择性 COX-2 抑制剂的配体。
方法
使用不同的光谱技术（FTIR、HNMR、CNMR）和元素分析对合成的类似物进行了表征。所有合成的化合物都进行了 COX-2 蛋白口袋结合潜力的筛选，并使用角叉菜胶诱导的爪肿胀法在动物中评估其抗炎潜力。进一步选择了 5 种化合物来评估其在乙醇诱导的大鼠胃溃疡模型中的体内抗溃疡活性。
结果
5 种化合物（2a、2b、3a、3b 和 3c）表现出很强的抗炎活性和在 COX-2 蛋白口袋中的显著结合潜力。同样，与标准药物奥美拉唑相比，这 5 种化合物表现出显著的胃保护作用（**p<0.01）。
结论
根据我们的结果，我们假设 2-取代苯并恶唑衍生物具有作为开发选择性抗炎药物（COX-2 抑制剂）的候选物的巨大潜力。然而，需要进一步评估来阐明它们的潜在机制。
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